This K23 proposal will complete Robert Dickson, MD's training towards his long-term career goal of improving our understanding and treatment of lung disease by investigation of the microbiome. Dr. Dickson is a Pulmonary and Critical Care physician and scientist at the University of Michigan with established success in the burgeoning field of lung microbiome studies. This proposal builds on Dr. Dickson's previously acquired expertise in pulmonary pathophysiology and microbial ecology with new training in clinical research methods and computational biology. These established and newly-acquired skills will be integrated to improve our understanding of the role of the microbiome in the pathogenesis of the Acute Respiratory Distress Syndrome (ARDS). This research will be conducted under the guidance of primary mentor Gary B. Huffnagle PhD, co- mentor Theodore J. Standiford MD and an advisory board of accomplished investigators with expertise in clinical research methods, computational biology and lung immunology as well as extensive mentoring success. This 5-year plan includes formal coursework, professional development, and progressively independent research, with defined milestones to ensure productivity and a successful transition to independence. The Acute Respiratory Distress Syndrome (ARDS) is a major cause of morbidity, mortality and expense, responsible for an estimated 74,500 U.S. deaths per year. Numerous studies have identified indirect evidence of translocation of bacteria from the gastrointestinal tract to the lung in patients at risk for ARDS, but to date no study has evaluated the role of microbiome in the pathogenesis of ARDS. This proposal will test the hypothesis that translocation of gut bacteria to the lung provokes the inflammation and injury of ARDS via two specific Scientific Aims. Aim 1 will determine if translocation of enteric bacteria to the lung microbiome precedes the clinical development of ARDS, and Aim 2 will determine the temporal relationship between respiratory dysbiosis, host inflammation and the clinical onset of ARDS. Inherent to completing these high-level aims, Dr. Dickson will execute a prospective cohort study of patients at high risk for ARDS, utilize modern culture-independent techniques of bacterial identification to describe the bacterial communities in the lungs and gastrointestinal tracts of high-risk patients, and apply novel techniques of advanced computational modeling to the complex nonlinear system of ARDS pathogenesis. This work will build to at least two R01 proposals: 1) to determine if the lung microbiome contributes to disease progression among patients with established ARDS and 2) to determine if the lung microbiome can be therapeutically manipulated in critically ill patients to prevent or modulate respiratory disease. n addition to building a foundation for a programmatic line of research to understand the role of the microbiome in lung disease, this proposal will provide Dr. Dickson with research skills applicable to additional domains of human microbiome and ARDS research. This K23 award will equip Dr. Dickson to establish himself as an independent investigator and international leader in this promising field.

Public Health Relevance

The Acute Respiratory Distress Syndrome (ARDS) is a major cause of morbidity, mortality and expense, responsible for an estimated 74,500 U.S. deaths per year; the National Institutes of Health have identified the prevention and early treatment of ARDS as a research priority. We lack an understanding of the pathogenesis of ARDS, impeding our ability to predict and prevent its onset. Determination of the role of the microbiome in the pathogenesis of ARDS would both 1) improve our ability to predict the onset of ARDS, enabling targeted preventive interventions and 2) identify novel therapeutic targets at the microbiome/host interface in patients at risk for ARDS.